The drugs used for the treatment of rheumatic diseases often have antiphlogistic as well as analgesic properties. For this reason they are used not only to treat chronic rheumatic diseases but also for acute rheumatic attacks and for acute pain treatment.
Many of these pharmaceutical compositions have only limited solubility and for this reason are absorbed only slowly by the body. In the treatment of acute pain, a rapid influx of active substance is essential to ensure that the activity sets in rapidly. It is therefore often necessary to increase the speed of dissolution and solubility of the active substances in question.
For known drugs in this field, different approaches have been adopted, e.g. ibuprofen and diclofenac are used in the form of their salts or piroxicam is used in the form of β-cyclodextrin inclusion compounds. However, when administered by oral route, these active substances do not always exhibit a sufficient plasma concentration for rapid effect within a short time. The pharmacokinetic differences of ibuprofen-lysinate compared with ibuprofenic acid are described for example in Int. J. Clin. Pharmacol., Ther. Toxicol. ,Vol. 27, No. 7, 324-328 (1989). It says that the average peak-plasma level measured on 8 fasting test subjects in the case of ibuprofen-lysinate (1000 mg, film-coated tablet) was achieved on average 0.55 h after administration and was 69.1: g/ml, whereas the corresponding values for ibuprofenic acid (600 mg, sugar-coated tablet) are given as 0.89 h and 50.8: g/ml. In non-fasting test subjects the differences lose statistical significance according to the authors and amount to 50.3: g/ml ibuprofen-lysinate after 1.18 h and 44.6 g/ml for ibuprofenic acid after 1.55 h. DE 37 00 172 explains that numerous NSAID's do not dissolve easily in water and are therefore not really suitable for preparing parenteral formulations. To overcome this problem, the use of N-(methyl)-glucamine and glucamine salts of a number of NSAIDs, including, inter alia, Isoxicam, Tenoxicam and Piroxicam has been proposed. A parenteral Piroxicam-N-(methyl)-glucamine formulation is described as Example 4. It is also stated that these salts can also be administered in oral, rectal or topical formulations, but the published application contains no information on the absorption of oral formulations. The problem described therein, namely the preparation of a parenteral aqueous formulation of a comparatively insoluble active substance, differs substantially from the objective of the present invention. As explained hereinafter, this consists in providing an orally administered solid pharmaceutical preparation of meloxicam which produces effective plasma levels soon after administration. In addition, the starting point of the present invention was considerably more difficult, as free meloxicam is less water-soluble, by a factor of about 10, than free piroxicam over a wide pH range (European Journal of Pharmaceutical Science 4 (1996), 175-187, particularly FIG. 10 on page 184).
Meloxicam (4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-carboxamide-1,1 -dioxide) is an antirheumatic which is distinguished by the fact that it is well tolerated by the stomach at the doses necessary for therapy. The active substance and its sodium salt—as well as its N-methyl-D-glucamine salt (meglumin salt) are described in EP-A-0 002 482. The anti-inflammatory and pain-relieving properties of meloxicam also make this active substance very interesting for use in pain therapy. However, the active substance has very low solubility in the acid range which prevails in the upper part of the gastrointestinal channel. It is therefore absorbed with a time delay after administration. Maximum plasma levels are reached within 2-8 hours, depending on the formulation. However, the activity is long-lasting and highly effective. As a rule, therefore, a single dose each day is sufficient. In order to open up this active substance, which is suitable for pain therapy, for treating acute conditions as well, it is necessary to ensure rapid absorption and, at the same time, a rapid onset of activity.